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Imaging P-glycoprotein function in rats using [11C]-N-desmethyl-loperamide

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Abstract

Objective

One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [11C]N-desmethyl-loperamide ([11C]dLop), for measuring P-gp function in the rat brain.

Methods

The precursor to [11C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [11C]methyl iodide. [11C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function.

Results

Plasma levels of parent [11C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60 min. In controls, brain uptake of [11C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70 min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA = 7.3, TQ = 4.7) compared to controls (no inhibitor = 2.1).

Conclusions

The rat brain demonstrates significantly increased uptake of [11C]dLop after P-gp inhibition. [11C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future.

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Acknowledgments

We thank the Columbia University PET center staff for their technical assistance. We also thank Paul E. Harris, PhD for his technical assistance. The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, 180 Fort Washington Ave. HP 3-305, New York, NY, 10032, USA

    Michael D. Farwell & Masanori Ichise

  2. Department of Clinical Analyzing Technology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minami tamagaki-cho, Suzuka, 513-8670, Japan

    Yasuhiko Iida

  3. Department of Neurology, New York University Langone Medical Center, 223 East 34th Street, New York, NY, 10016, USA

    Derek J. Chong

  4. Department of Psychiatry, Columbia University Medical Center, 1051 Riverside Drive, New York, NY, 10032, USA

    Sung A. Bae & Balu Easwaramoorthy

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  1. Michael D. Farwell
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  2. Derek J. Chong
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  3. Yasuhiko Iida
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  4. Sung A. Bae
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Correspondence to Michael D. Farwell.

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Farwell, M.D., Chong, D.J., Iida, Y. et al. Imaging P-glycoprotein function in rats using [11C]-N-desmethyl-loperamide. Ann Nucl Med 27, 618–624 (2013). https://doi.org/10.1007/s12149-013-0725-5

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  • DOI: https://doi.org/10.1007/s12149-013-0725-5

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